Surfactants, lipids, and polymer molecules that have both polar and nonpolar components are termed as amphiphilic molecules. The hydrophobic effect drives the amphiphilic molecules in polar solvents to spontaneously self-assemble into a rich array of thermodynamically stable lyotropic liquid crystalline phases. The liquid crystalline phases possess a sufficient average degree of molecular orientational order, characterized by their structural symmetry, and are often formed in aqueous surfactant systems at relatively high amphiphile concentration.
The molecular structures of lipids play an important role in the determination of phase behavior. The critical packing parameter (P) is used to predict the nanostructure of formed liquid crystal with the formula P=v/a l, where P is critical packing parameter, ‘v’ is the hydrophobic chain volume, ‘a’ is the cross-sectional area of the polar headgroup, and ‘l’ is the hydrophobic chain length.
When, P<1, oil-in-water self-assembled structures are formed, such as normal micelles (L1), normal cubic structure (V1), and normal hexagonal phases (H1). When P>1, water-in-oil self-assembled structures are formed, such as reversed micelles (L2), reversed cubic structure (V2), and reversed hexagonal structure (H2).
There are several different types of lyotropic liquid crystal structures where each of these different types has a different extent of molecular ordering within the solvent matrix. One such example is the bicontinuous cubic liquid crystalline phase.
Lipids, such as glycerol monooleate form mesophase structures that are thermodynamically stable, such as the bicontinuous phases with Ia3d and Pn3m symmetry. Phases such as the Pn3m are stable in the presence of excess water. Therefore, they are amenable to formulation as particle dispersions. These phases can be loaded with drugs that can be subsequently released. The fact that these are thermodynamically stable makes them especially suitable for pharmaceutical formulations.
One main problem with these phases, especially for the particle dispersions is that they give a burst release of loaded drugs. Therefore, control of the release rate is currently difficult and is of significant importance to pharmaceutical applications.
It is therefore important to provide composition and the processes for stabilizing fluid amphiphile interfaces. Since the advent of the first patent in 1984 [EP0126751] when the highly ordered cubic phase was proposed as an interesting matrix in controlled release preparations, lipid-based liquid crystal systems have been extensively investigated in drug delivery, as well as the potential application in theranostic nanomedicines. These prior art have mainly taught the use of bicontinuous micellar phases for applications in drug delivery and theranostics. However, rapid release of hydrophilic drugs from such bicontinuous phases limits their applications. Therefore, controlled decrease of the release rate of encapsulated drugs is of great importance.
This is made possible by forming inverse discontinuous micellar phases such as the Fd3m symmetry phase.
Discontinuous cubic phases are intermediate liquid crystalline phases and reside between hexagonal phases and micelles. Discontinuity is attributed to discretely ordered aggregates of micellar structures and hence either the water or hydrocarbon phase is discontinuous.
Article titled ‘Oil-Loaded Monolinolein-Based Particles with Confined Inverse Discontinuous Cubic Structure (Fd3m)’ by Anan Yaghmur et.al published in Langmuir, 2006, 22 (2), pp 517-521 reports discontinuous micellar cubic phase of the symmetry Fd3m consisting of MLO (monolinolein)—water—TC (tetradecane) system at a specific TC/MLO weight ratio with TC-loaded aqueous dispersions in the confined intermediate phase i.e Fd3m phase. The article discloses the use of ahydrophobic additive, tetradecaneoil to modulate the texture of liquid crystals which result in phase transition.
Further, an interesting property of the cubic phases formed by certain classes of amphiphiles is their ability to be dispersed into particles, termed cubosomes. Cubosomes are liquid crystalline nanostructured particles with the same unique properties of the bulk cubic phase, although cubosome dispersions have much lower viscosity.
Cubic phases are used to improve the drug bioavailability and reduce drug toxicity. Yang et al. [Z. Yang, Y. Tan, M. Chen et al., “Development of amphotericin B-loaded cubosomes through the SolEmuls technology for enhancing the oral bioavailability,” AAPS PharmSciTech, vol. 13, no. 4, pp. 1483-1491, 2013.74] prepared PT-based cubosomes containing amphotericin B (AmB) to improve its bioavailability and reduce nephrotoxicity. Esposito et al. [E. Esposito, R. Cortesi, M. Drechsler et al., “Cubosome dispersions as delivery systems for percutaneous administration of indomethacin,” Pharmaceutical Research, vol. 22, no. 12, pp. 2163-2173, 200596] studied the performance of cubosomes as sustained percutaneous delivery systems with the model drug molecule of indomethacin.
The present inventors observed that formation of Fd3m phases, however, requires the addition of significant quantities of nonpolar materials (such as oils) making the process of formulation more difficult.
With a view to design adequate mesophase delivery system for sustained release of the drug, the present invention provides a composition using lipid and small quantities of hydrophilic polymer with a well-defined size and compact shapecapable of inducing sufficient curvature in the lipid assembly to form an Fd3m phase effortlessly.
The use of hydrophilic polymers in formation of reverse micellar phases is disclosed in US2005079145, WO2013030838 or KR20090027809, however, said applications fail to disclose the use of hydrophilic polymers in lipid/water system to induce Fd3m phase for sustained release of the therapeutic drugs or biologically active component.